Despite the recent introduction of cyclosporine, optimal results of clinical transplantation can be anticipated only if rejection is avoided without the dangers of non specific immunosuppressive agents. We and others have obtained considerable evidence that rejection may not be initiated if passenger leukocytes with antigen presenting capability (such as macrophages) are removed from allografts. We also previously made the unexpected observation that this method is only effective if donor and host are major histocompatibility complex (MHC) incompatible. We have formed the hypothesis that if donor and recipient are MHC compatible, host antigen presenting cells (APCs) can deputize for those of the donor. However, restriction precludes MHC incompatible host APCs from substituting for those of the donor. For testing this hypothesis, several strategies will be used to delete passenger cells from allografts (e.g., culture in high oxygen tension, ultraviolet irradiation, prolonged parking of grafts in intermediate hosts). In addition to endocrine grafts such as pancreatic islets, skin and vascularized heart allografts will be studied. A number of combinations of inbred strains of rats and mice, as well as congenic animals, will be used to fully test the hypothesis.